A cartilage is one of a small number of blood vessel-free tissues in vivo, and it is said that it is difficult to reconstruct its original tissue. In order to suppress the occurrence of osteoarthritis based on the localized change of the cartilage to a morbid state, such as a cartilage defect caused by an external injury or dissecting osteochondropathy, various remedies have been tried.
Autologous chondrocytes implantation (ACI) in which only the cell of a chondrocyte obtained by sampling a mesenchymal stem cell from autologous chondrocytes or bone marrow cells and differentiating it, or the chondrocyte cultured in a scaffold is implanted to a cartilage defective region has been tried (refer to N Engl J Med. 331, 889-95 (1994), J Bone Joint Surg Am. 76, 579-92 (1994) and Artificial Organs. 25, 172-179 (2001)).
To culture an autologous chondrocyte in vitro, 3-D culture for creating an environment close to the environment in vivo is tried energetically, and a material which is recognized as safe in vivo, such as collagen, alginic acid or fibrin is used as a scaffold. As for collagen out of these, Ochi et al. have developed a method using aterocollagen and have started clinical tests (JP-A 2001-293081).
Although collagen exhibits bio-absorptivity, it has problems that it is difficult to completely remove its antigenicity and that the possibility of its infection with an unknown virus cannot be denied.
In contrast to this, hyaluronic acid is a constituent of an extracellular matrix forming the cartilage of a joint and having high affinity for the cartilage. Further, as hyaluronic acid can be formed by fermentation without a raw material derived from an animal, the possibility of infection with an unknown virus is low unlike collagen. Therefore, studies on the treatment of an injury to the cartilage of a knee using hyaluronic acid are now under way for regenerative medical treatment.
U.S. Pat. No. 5,939,323, J. Biomed. Mater. Res. 42, 172-81 (1998), J. Biomed. Mater. Res. 46, 337-46 (1999) and J. Orthop. Res. 18, 773-780 (2000) disclose benzyl esterified hyaluronic acid. JP-A 7-97401 discloses bisepoxide crosslinked hyaluronic acid. Further, U.S. Pat. No. 4,582,865 and U.S. Pat. No. 4,605,691 disclose divinylsulfone crosslinked hyaluronic acid, JP-A 60-130601 discloses formaldehyde crosslinked hyaluronic acid, and JP-A 60-130601 discloses formaldehyde crosslinked hyaluronic acid. Other hydrazide crosslinked hyaluronic acids are known.
However, crosslinking agents are used to improve the bio-absorptivity of hyaluronic acid in all of the above prior arts. Since these crosslinking agents are non-bioabsorptive, the safety of the agents is concerned, and a highly safe material for treating the cartilage of a joint is desired. The term “crosslinking” as used herein means not only chemical crosslinking by covalent bonding but also ion crosslinking by electrostatic interaction and physical crosslinking by van der Waals force or hydrophobic interaction.